The proto-oncogene ras is the most frequently mutated oncogene in human cancer, occurring in approximately 30% to 40% of all tumors. The ras genes encode small membrane associated GTP binding proteins that function in transmitting extracellular signals that regulate cell proliferation and differentiation. Ras activation or oncogenic mutation leads to the activation of signal transduction pathways that ultimately activate kinases that directly stimulate transcription factors such as Ets-1/2, Elk-1 or c-jun. These transcription factors then activate genes involved in controlling cellular proliferation. Recently, we have shown that expression of genes involved in immune and inflammatory responses, growing evidence indicates that this transcription factor and its family members are involved in controlling cellular proliferation. Typically, the activation of NF- kappaB (following treatment of cells with inflammatory cytokines, T cell activation signals, LPS, etc.) involves the targeted phosphorylation and degradation of the NF-kappaB inhibitor known as IkappaB, allowing nuclear translocation of NF-kappaB. However, we have show that both Ras and Raf transformed cells exhibit enhanced kappaB-dependent gene but do not exhibit enhanced nuclear translocation of NF-kappaB. Consistent with this observation, we find that the transcriptional activation function of the RelA/p65 subunit of NF-kappaB (existing in relatively low nuclear levels) is functionally activated in Ras or Raf transformed cells. Supportive of a role for NF-kappaB in mediating cellular transformation by Ras, we find that (a) expression of a super-repressor form of IkappBalpha blocks focus formation induced by oncogenic Ras, (b) p65 null fibroblast are inefficient at activating kappaB-dependent transcription in response to Ras, (c) the super-repressor IkappaBalpha blocks tumorigenesis of Ras-expressing and BCR-ABL- expressing tumor cell lines, and (d) inhibition of NF-kappaB function leads to apoptosis of Ras transformed cells. How NF-kappaB is target to respond to Ras and the exact role that NF-kappaB plays in controlling oncogenesis/tumorigenesis mediated by Ras are presently unknown. In order to address these questions and to explore the therapeutic potential of inhibiting NF-kappaB, the following aims are proposed: (1) determine how oncogenic Ras activates the transcription all activation function of NF-kappaB, (2) determine the role that NF- kappaB plays in controlling Ras mediated tumorigenesis and in controlling cell survival in response to Ras activation, and (3) determine if the inhibition of NF-kappaB, either alone or in combination with standard cancer therapies, will lead to significant tumor regression. The data will provide important new insights into regulation and function of a downstream effector of Ras signaling and will likely provide new therapeutic routes to cancer treatment.